Extracellular Matrix Modulates Outgrowth Dynamics in Ovarian Cancer.
Extracellular Matrix Modulates Outgrowth Dynamics in Ovarian Cancer.
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DOI：
10.1002/adbi.202200197
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发表时间：
2022-12
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
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卵巢癌 (OC) 形成从受累器官外表面延伸至腹膜的增生。对 OC 生长物的形成知之甚少，因为用于检查形成生长物的细胞组件的行为的 OC 细胞培养模型的可用性有限。在代表未经治疗和化疗恢复的 OC 的人体组织中，对细胞外基质 (ECM) 成分、层粘连蛋白 γ1 和胶原蛋白进行免疫化学评估，我们开发了富含层粘连蛋白和胶原蛋白的 ECM 重建细胞培养模型，适合研究可形成增生的细胞簇。我们证明 ECM 促进表达突变体 p53-R175H 的输卵管非纤毛上皮细胞 (FNE) 和各种 OC 细胞系的生长形成。生长物是由经历向外易位的细胞启动的，并且在机械分离后，可以插入间皮细胞单层。电子显微镜、光学相干断层扫描 (OCT) 和小振幅振荡剪切实验表明，高 ECM 浓度增加了 ECM 纤维网络厚度，并导致 ECM 环境中的高剪切弹性。这些身体特征与抑制生长有关。低 ECM 浓度的培养环境模拟恶性腹膜液（腹水）的粘弹性，并支持细胞增殖、细胞易位和生长形成。这些结果强调了 ECM 微环境在调节 OC 生长中的重要性，并可以为为什么原发性和复发性卵巢肿瘤形成伸入腹膜腔的生长提供额外的解释。本研究探讨了不同细胞外基质浓度在调节卵巢癌生长中的重要性。它表明细胞外基质促进表达突变型p53的输卵管非纤毛上皮细胞和各种卵巢癌细胞系中的生长物形成。低但不是高浓度的细胞外基质模拟恶性腹膜液的粘弹性并支持细胞增殖、细胞易位和生长形成。
Ovarian carcinoma (OC) forms outgrowths that extend from the outer surface of an afflicted organ into the peritoneum. OC outgrowth formation is poorly understood because there is limited availability of OC cell culture models to examine the behavior of cell assemblies that form outgrowths. Prompted by immunochemical evaluation of extracellular matrix (ECM) components, laminin γ1 and collagens, in human tissues representing untreated and chemotherapy-recovered OC, we developed laminin- and collagen-rich ECM-reconstituted cell culture models amenable to studies of cell clusters that can form outgrowths. We demonstrate that ECM promotes outgrowth formation in fallopian tube non-ciliated epithelial cells (FNE) expressing mutant p53-R175H and various OC cell lines. Outgrowths were initiated by cells that had undergone outward translocation and, upon mechanical detachment, could intercalate into mesothelial cell monolayers. Electron microscopy, optical coherence tomography (OCT), and small amplitude oscillatory shear experiments revealed that high ECM concentration increased ECM fibrous network thickness and led to high shear elasticity in the ECM environment. These physical characteristics were associated with the suppression of outgrowths. A culture environment with low ECM concentration mimicked viscoelasticity of malignant peritoneal fluids (ascites) and supported cell proliferation, cell translocation, and outgrowth formation. These results highlight the importance of ECM microenvironments in modulating OC growth and could provide an additional explanation of why primary and recurrent ovarian tumors form outgrowths that protrude into the peritoneal cavity. This study investigates the importance of varying extracellular matrix concentration in modulating ovarian cancer growth. It demonstrates that extracellular matrix promotes outgrowth formation in fallopian tube non-ciliated epithelial cells expressing mutant p53 and various ovarian cancer cell lines. Low but not high concentrations of extracellular matrix mimic viscoelasticity of malignant peritoneal fluids and support cell proliferation, cell translocation, and outgrowth formation.